Treatment of HIV-1 infected patients with combinations of inhibitors of the viral protease (PR) and reverse transcriptase (RT) enzymes has been remarkably successful in suppressing viral replication and prolonging patient survival. However, extended administration of these antiretroviral (ARV) agents is commonly associated with the emergence of resistant virus that often compromises treatment. The clinical management of ARV treatment experienced patients has been greatly facilitated by the development of phenotypic and genotypic drug resistance assays. The increase in the prevalence and spread of drug-resistant virus, including strains displaying broad cross-resistance to PR and RT inhibitors has necessitated the development of new therapeutic approaches to combat this highly adaptive virus. Inhibitors of HIV entry represent a promising new class of antiretroviral agents. The development of phenotypic and genotypic assays to detect drug resistant strains will undoubtedly accelerate the development of entry inhibitors and improve their utility in the clinic. Phase I support was used to develop a phenotypic assay that measures susceptibility of HIV-1 to entry inhibitors and a genotypic assay that detects resistance mutations in the HIV-1 envelope gene. Phase II support is intended to optimize, scale and validate these two resistance tests for routine use in a clinical reference laboratory environment.